Process for Making N-Hydroxy-3[4-[[[2-(2methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and Starting Materials Therefor

a technology of n-hydroxy and phenyl, which is applied in the field of making n-hydroxy-3[4-[ and starting materials therefor, can solve the problems of synthesis of n-hydroxy-3[4-[, inability of inventor to make this compound, and limited success of inventor to achieve i

Active Publication Date: 2012-01-12
PHARMA& SCHWEIZ GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Previous attempts by the inventors to make this compound have had limited success due to the presence of various impurities and by-products in the reaction product; the removal of such impurities and by-products requires lengthy and tedious reworking / re-crystallization of the desired product.
Thus, synthesis of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide has heretofore been complicated, time-consuming and limited to small-scale synthesis.

Method used

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  • Process for Making N-Hydroxy-3[4-[[[2-(2methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and Starting Materials Therefor
  • Process for Making N-Hydroxy-3[4-[[[2-(2methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and Starting Materials Therefor
  • Process for Making N-Hydroxy-3[4-[[[2-(2methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and Starting Materials Therefor

Examples

Experimental program
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example 1

Preparation of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]pheny]-2E-2-propenamide

[0049](E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]phenyl)-acrylic acid methyl ester hydrochloride salt (90g, 233.8 mmole) is placed in a 4-necked reaction flask and methanol (475 g) is added. The suspension is cooled to −15° C. A solution of sodium hydroxide (28.2 g, 705 mmole) in methanol (419.2 g) is added to the suspension at −15° C. (addition time ca. 30 minutes), followed by the addition of the hydroxylamine solution (100.3 g of a 50% solution in water, corresponding to 50.15 g hydroxylamine, 1518 mmole) at, this temperature (addition time ca. 30 minutes). Caution: it is important to use different addition funnels for the sodium hydroxide and hydroxylamine solutions respectively. Stirring is continued at −15° C. for an additional 7 hours until a conversion of >99.5 area % is achieved according to HPLC. The reaction mixture is warmed to 0° C., stirred for 5 hours at ...

example 2

Preparation of (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-Acrylic Acid Methyl Ester Hydrochloride Salt

[0050]2-Methyltryptamine (100 g, 573.8 mmole) and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester (115 g, 604.6 mmole) are dissolved in methanol (1250 mL). The solution is stirred for 1 hour at 20-25° C., to allow the formation of the imine intermediate. The solution is diluted with methanol (1250 mL) and cooled to −15° C. Sodium borohydride (16.25 g, 429.5 mmole) is added in several portions during ca. 1 hour while maintaining the temperature at −15° C. to −10° C. The reaction mixture is stirred for additional 30 minutes at this temperature and the reaction is quenched by slow addition of the reaction mixture onto a pre-cooled solution of hydrochloric acid (488 g concentrated hydrochloric acid in 337 g of water and 198 g of methanol) at 0-5° C. A suspension is formed. The addition funnel is rinsed with methanol (40 g) and the temperature is raised to 60-65°...

example 3

Preparation of (E)-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl]-phenyl)-Acrylic Acid methyl Ester Hydrochloride Salt

[0051]2-Methyltryptamine (50 g, 287 mmole) and (E)-3-(4-formyl-phenyl)-acrylic acid methyl ester (54.6 g, 287 mmole) are suspended in methanol (514 g). The solution is stirred for 1 hour at 20-25° C., to allow the formation of the imine intermediate. The solution is cooled to −15° C. within ca. 20 minutes. Sodium borohydride (5.43 g, 143.5 mmole) is added in several portions during ca. 1 hour while maintaining the temperature at −15° C. to −10° C. The reaction mixture is stirred for additional 30 minutes at this temperature and the temperature is raised to 20-25° C. within ca. 25 minutes. The reaction mixture is stirred for 30 minutes at 20-25° C. and water (80 g) is slowly added while maintaining the temperature at 20-25° C. An aqueous solution of hydrochloric acid (70.5 g concentrated HCl in 50 g of water) is slowly added to the reaction mixture such that th...

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Abstract

N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and starting materials therefore are prepared by new synthetic methods.

Description

BACKGROUND OF THE INVENTION[0001]This application is a continuation application of Ser. No. 12 / 302,572, filed Nov. 26, 2008, which is a National Phase application of PCT / US2007 / 070564, filed Jun. 7, 2007, which claims benefit of Provisional application No. 60 / 867,878, filed Nov. 30, 2008 and Provisional application No. 60 / 804,527, filed Jun. 12, 2006.FIELD OF THE INVENTION[0002]This invention relates to a process of making N-hydroxy-3-[4-[[[2-(2-methyl process for making n-hydroxy-3-[4-[[[2-(2-methyl-1h-indol-3-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide and starting materials therefore.RELATED BACKGROUND ART[0003]The compound N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide (alternatively, N-hydroxy-3-(4-{[2-(2-methyl-1H-indol-3-yl)-ethylamino]-methyl}-phenyl)-acrylamide) has the formula[0004]as described in WO 02 / 22577. Valuable pharmacological properties are attributed to this compound; thus, it can be used, for example, as a h...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): C07D209/20
CPCC07D209/16A61P35/00A61P43/00C07D207/16C07D207/14C07D207/20C07D207/04
InventorACEMOGLU, MURATBAJWA, JOGINDER S.PARKER, DAVID JOHNSLADE, JOEL
OwnerPHARMA& SCHWEIZ GMBH